Abstract | OBJECTIVE: METHODS: RESULTS: In an in vitro osteoclastogenesis model, PPI-2458 potently inhibited osteoclast differentiation and bone resorption. In the rat PG-PS arthritis model, PPI-2458 afforded significant protection against established disease after therapeutic dosing. This in vivo activity of PPI-2458 was linked to the inhibition of methionine aminopeptidase type 2. Histopathologic assessment of affected joints showed improvement in processes of inflammation, bone resorption, and cartilage erosion, associated with significant improvement in all clinical indices. The protective effects of PPI-2458 against bone destruction in vivo, including the structural preservation of affected hind joints, correlated with improvements in bone histomorphometric markers, as determined by microfocal computed tomography and a significant decrease in systemic C-telopeptide of type I collagen, suggesting decreased osteoclast activity in vivo. Moreover, PPI-2458 prevented cartilage erosion as shown by a significant decrease in systemic cartilage oligomeric matrix protein. CONCLUSION: The findings of this study suggest that PPI-2458 exerts disease-modifying activity in experimental arthritis through its direct inhibition of several pathophysiologic processes of this disease. These results provide a rationale for assessing the potential of PPI-2458 as a novel RA therapy.
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Authors | Gerhard Hannig, Sylvie G Bernier, Jennifer G Hoyt, Beth Doyle, Ed Clark, Russell M Karp, Jeanine Lorusso, William F Westlin |
Journal | Arthritis and rheumatism
(Arthritis Rheum)
Vol. 56
Issue 3
Pg. 850-60
(Mar 2007)
ISSN: 0004-3591 [Print] United States |
PMID | 17328059
(Publication Type: Journal Article)
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Chemical References |
- Enzyme Inhibitors
- Epoxy Compounds
- Glycoproteins
- PPI 2458
- Peptidoglycan
- Polysaccharides
- Aminopeptidases
- Metap2 protein, rat
- Valine
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Topics |
- Aminopeptidases
(antagonists & inhibitors)
- Animals
- Arthritis, Rheumatoid
(chemically induced, drug therapy, pathology)
- Bone Resorption
(pathology)
- Cell Differentiation
(drug effects)
- Cells, Cultured
- Disease Models, Animal
- Enzyme Inhibitors
(pharmacology, therapeutic use)
- Epoxy Compounds
(pharmacology, therapeutic use)
- Female
- Glycoproteins
(antagonists & inhibitors)
- Humans
- Joints
(pathology, physiopathology)
- Osteoclasts
(drug effects, pathology)
- Peptidoglycan
- Polysaccharides
- Rats
- Rats, Inbred Lew
- Severity of Illness Index
- Valine
(analogs & derivatives, pharmacology, therapeutic use)
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